19-35871871-C-T

Variant names:

• chr19-35871871-C-T
• rs375123845
• NM_001024807.3:c.685C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001024807.3(APLP1):​c.685C>T​(p.Arg229Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: APLP1 NM_001024807.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89

Genes affected

APLP1 (HGNC:597): (amyloid beta precursor like protein 1) This gene encodes a member of the highly conserved amyloid precursor protein gene family. The encoded protein is a membrane-associated glycoprotein that is cleaved by secretases in a manner similar to amyloid beta A4 precursor protein cleavage. This cleavage liberates an intracellular cytoplasmic fragment that may act as a transcriptional activator. The encoded protein may also play a role in synaptic maturation during cortical development. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29594967).
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APLP1	NM_001024807.3	c.685C>T	p.Arg229Trp	missense_variant	Exon 6 of 17	ENST00000221891.9	NP_001019978.1
APLP1	NM_005166.5	c.685C>T	p.Arg229Trp	missense_variant	Exon 6 of 17		NP_005157.1
APLP1	XM_017026737.3	c.685C>T	p.Arg229Trp	missense_variant	Exon 6 of 16		XP_016882226.1
APLP1	XM_017026738.3	c.685C>T	p.Arg229Trp	missense_variant	Exon 6 of 16		XP_016882227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APLP1	ENST00000221891.9	c.685C>T	p.Arg229Trp	missense_variant	Exon 6 of 17	1	NM_001024807.3	ENSP00000221891.4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152144 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000800 AC: 20 AN: 250048 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000798

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000800 AC: 117 AN: 1461700 Hom.: 0 Cov.: 32 AF XY: 0.0000798 AC XY: 58 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152144 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74308

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.685C>T (p.R229W) alteration is located in exon 6 (coding exon 6) of the APLP1 gene. This alteration results from a C to T substitution at nucleotide position 685, causing the arginine (R) at amino acid position 229 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.;.;.;T
Eigen	Benign	0.043
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.81	.;L;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.8	N;N;.;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.010	D;D;.;.;.
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.50
MVP		0.73
MPC		1.1
ClinPred		0.22	T
GERP RS		2.4
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs375123845; hg19: chr19-36362773; COSMIC: COSV55704274; COSMIC: COSV55704274;